Activity of T-705 in a Hamster Model of Yellow Fever Virus Infection in Comparison with That of a Chemically Related Compound, T-1106

Abstract

Treatment with the nucleoside analog T-1106 was previously shown to be effective in a hamster model of yellow fever virus (YFV) disease, even though it had only slight activity in cell culture. In the study described in this report, the activity of T-705, a chemically related compound currently undergoing clinical trials for the treatment of influenza (FDANews 4:1, 2007), was tested against YFV in cell culture and in the hamster model. The antiviral efficacy of T-705 in cell culture occurred at a concentration of 330 M, which was more than threefold lower than the concentration at which T-1106 had antiviral efficacy, as determined by a virus yield reduction assay and confirmed by a luciferase-based ATP detection assay. Time-of-addition studies revealed that addition of T-705, T-1106, or ribavirin at 0, 4, 8, or 12 h after virus challenge was effective in inhibiting virus in Vero cells, suggesting that these three agents have similar mechanisms of action in cell culture. Because of its more potent activity in cell culture, it was anticipated that T-705 treatment of hamsters infected with YFV would result in protection from disease. Significant improvements in survival and disease parameters were seen in infected animals when T-705 was administered orally at a dose of 200 or 400 mg/kg of body weight per day when it was given twice a day for 8 days. Significant improvements were also observed with a dose of 400 mg/kg/day when treatment initiation was delayed as late as 3 days after virus inoculation. Although the dose of T-705 required for efficacy in hamsters is higher than that of T-1106 required for efficacy, T-705 treatment is effective in significantly improving disease parameters in YFV-infected hamsters, which may indicate its potential utility in the treatment of YFV disease in humans.

T-705 (favipiravir) activity against lethal H5N1 influenza A viruses

“…Similar results have been obtained in canine cells (17). To date, the potent inhibitory effects of T-705 have been demonstrated against various RNA viruses, including H1N1, H2N2, and H3N2 influenza A virus, influenza B and C viruses, poliovirus, rhinovirus, and respiratory syncytial virus (16), West Nile virus (28), yellow fever virus (29), and arena virus (30) in cultured cells and mammalian animal models, but not against DNA viruses, such as herpes simplex virus type 1, human cytomegalovirus, and adenovirus (16). Although further mechanistic studies are required with these RNA viruses, it is likely that T-705 inhibits their RNA-dependent RNA polymerase activity (20).…”

“…After cellular debris was removed by centrifugation at 3,000 × g for 10 min, supernatants were subjected to plaque assays in MDCK cells. The research protocol for animal experiments was approved by the Animal Experiment Committee of the Institute of Medical Science, the University of Tokyo (approval number [19][20][21][22][23][24][25][26][27][28][29].…”

Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential

“…The YF virus (YFV) is an ssRNA virus of the Flaviviridae family responsible for over 30,000 deaths worldwide (45). Although an effective vaccine exists, periodic outbreaks continue to occur, and no antiviral agent has as yet been developed to treat , and both Rac1 and squalamine (E), respectively, in the presence of a coarsegrained membrane in which 20% of the lipids are charged.…”

“…Serum ALT in this cohort was within the normal range, suggesting minimal virus infection of the liver. We compared the effect of squalamine with ribavirin, an antiviral agent that has been well-studied in this model (45,48,49). Ribavirin was administered in a two times daily dosing regimen at 3.2, 10, and 32 mg/kg through the normal i.p.…”

“…In each animal, viral infection of the liver and endothelium occurs. Both the YF (45) and MCMV (46) infection models have been used to evaluate human therapeutic candidates. No drug has been reported to impact survival or viremia during EEEV infection in the hamster.…”